2. Higher rates of adverse events were noted among patients randomized to the FOLFIRINOX group.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Pancreatic adenocarcinoma is an aggressive cancer type with a grim prognosis after diagnosis. Standard of care for metastatic pancreatic cancer consists of surgical resection followed by the use of adjuvant gemcitabine or fluorouracil plus leucovorin. In this current analysis, researchers conducted a phase 3 randomized control trial to study the comparative efficacy of a novel chemotherapy regimen, modified FOLFIRINOX, composed of oxaliplatin, leucovorin, irinotecan, and fluorouracil versus gemcitabine as an adjuvant therapy after surgical cancer resection. Both regimens were studied for their effects on disease-free and overall survival, as well as overall safety and toxic effects. At a median follow-up of 33.6 months, researchers found that FOLFIRINOX treatment resulted in longer overall and disease-free survival rates compared to gemcitabine. Patients randomized to receive FOLFIRINOX were also noted to have higher rates of grade 3 or 4 adverse events.

These results are preliminary as many patients remained alive at the end of the study period, however they could point to the potential use of modified FOLFIRNOX as a new chemotherapy regimen for pancreatic cancer patients. Strengths of the study include its randomized design and extensive subgroup analysis. Limitations include the limited follow-up period and use of disease-free survival as the primary end-point.

In-Depth [randomized controlled trial]: This phase three, multicenter, open-label randomized control trial enrolled 493 patients across 77 hospitals in France and Canada. Patients were randomized in a 1:1 ratio to either receive FOLFIRINOX (n=247; dosed as oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 180 mg/m2, fluorouracil 2400 mg/m2) or gemcitabine (n=246, at a dose of 1000 mg/m2 ). The primary outcome of this analysis was disease-free survival among both study groups. Secondary outcomes included overall survival rates, metastasis-free survival, cancer-specific survival, and safety profiles of each regimen. Patients in the FOLFIRINOX group received a median of 12 cycles of treatment (range 1 to 12) with an average duration of 24.6 weeks (2 to 36.6 weeks) compared to 6 cycles (range 1 to 6) across 24.0 weeks (range 3.0 to 36.0 in the gemcitabine group). The median follow-up period in the intention to treat population was 33.6 months (95% confidence interval [CI], 30.3 to 36.0). Median disease-free survival rates were 21.6 months in the FOLFIRINOX group (95% CI, 17.7 to 27.6) as compared to 12.8 months in the gemcitabine group (95% CI, 11.7 to 15.2; stratified hazard ratio [HR], 0.58; 95% CI, 0.46 to 0.73; P<0.001). Median overall survival was 54.4 months in the FOLFIRINOX group (95% CI, 41.8 to unspecified) versus 35.0 months in the gemcitabine group (95% CI, 28.7 to 43.9; stratified HR for death, 0.64; 95% CI, 0.48 to 0.86; P=0.003). Grade 3 or 4 adverse events were reported in 75.9% of patients in the FOLFIRNOX group and 52.9% of patients in the gemcitabine group, and most commonly consisted of diarrhea, paresthesia, fatigue, peripheral sensory neuropathy, vomiting, abdominal pain and mucositis.

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